EP3740191B1 - Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant - Google Patents

Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant Download PDF

Info

Publication number
EP3740191B1
EP3740191B1 EP19701154.7A EP19701154A EP3740191B1 EP 3740191 B1 EP3740191 B1 EP 3740191B1 EP 19701154 A EP19701154 A EP 19701154A EP 3740191 B1 EP3740191 B1 EP 3740191B1
Authority
EP
European Patent Office
Prior art keywords
cyclodextrin
bilastine
pharmaceutical composition
ophthalmic pharmaceutical
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP19701154.7A
Other languages
German (de)
English (en)
Other versions
EP3740191A1 (fr
Inventor
Gonzalo HERNÁNDEZ HERRERO
Ana GONZALO GOROSTIZA
Pablo MORÁN POLADURA
Arturo ZAZPE ARCE
Nieves FERNÁNDEZ HERNANDO
Tania GONZÁLEZ GARCÍA
Paloma Tato Cerdeiras
Francisco Javier Otero Espinar
Anxo FERNÁNDEZ FERREIRO
Victoria DÍAZ TOMÉ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Faes Farma SA
Original Assignee
Faes Farma SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Faes Farma SA filed Critical Faes Farma SA
Priority to SI201930076T priority Critical patent/SI3740191T1/sl
Priority to EP21169956.6A priority patent/EP3915539A1/fr
Priority to PL19701154T priority patent/PL3740191T3/pl
Publication of EP3740191A1 publication Critical patent/EP3740191A1/fr
Application granted granted Critical
Publication of EP3740191B1 publication Critical patent/EP3740191B1/fr
Priority to HRP20211037TT priority patent/HRP20211037T1/hr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics

Definitions

  • the present invention relates to aqueous pharmaceutical compositions containing a high concentration of bilastine suitable for once daily administration and their use as antihistamine and antiallergic ophthalmic pharmaceutical compositions.
  • histamine plays a very important role in allergic-type diseases, such as allergic rhinitis, conjunctivitis, rhinoconjunctivitis, dermatitis, urticaria and asthma.
  • Antihistaminic compounds acting at the Hi-receptor histamine level are useful for treating such conditions.
  • Topical agents are superior, with faster onset of action (within minutes) than systemic agents, and, thus, are readily able to retard the allergic response.
  • Oral antihistamines can offer relief from other symptoms of allergy besides just ocular, but have a delayed onset of action when compared with topical ocular agents.
  • Topical antihistaminic agents also have fewer adverse effects than systemic antihistamines because of the lower doses required to penetrate the conjunctivae and the negligible serum levels from topical use.
  • Patent application EP 3040334 A1 also discloses benzimidazole compounds having potent selective H 1 antihistaminic activity, lacking activity on the central nervous system and on the cardiovascular system.
  • a particular compound with the above properties is 2-[4-(2- ⁇ 4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid, also known as bilastine, having formula: and developed by Faes Farma, Spain.
  • Bilastine is a H 1 antagonist benzimidazole compound with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism.
  • bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria.
  • EP 2709610 B1 discloses a topical ophthalmic solution containing a high concentration of olopatadine and the Food and Drug Administration (FDA) approved recently a new formulation of 0.77% olopatadine hydrochloride ophthalmic solution.
  • FDA Food and Drug Administration
  • Patent application WO 9413299 A1 discloses ophthalmic solutions of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole, otherwise known as emedastine.
  • emedastine Despite structurally similar to bilastine -emedastine is a benzimidazole derivative comprising an ethoxyethyl chain bound to the nitrogen atom of the imidazole ring-, the aqueous solubility of emedastine is much higher than that of bilastine which allows the provision of ophthalmic solutions comprising emedastine (at concentrations around 8 mg/mL) and with common excipients known to the skilled person such as EDTA, NaCl, hydroxypropyl methylcellulose (HPMC) and pH regulators NaOH/HCI and tris(hydroxymethyl)aminomethane.
  • EDTA EDTA
  • NaCl hydroxypropyl methylcellulose
  • US2007265247 discloses a topical formulation comprising bilastine.
  • WO 03089425 A1 discloses that bilastine can be used for ophthalmic solutions but fails to provide any technical details on how to successfully prepare said solutions.
  • WO 2007047253 A2 discloses methods of increasing the aqueous solubility of an antifungal azole using a hydroxybutenyl cyclodextrin.
  • WO 2009003199 A1 discloses aqueous solution formulations comprising a corticosteroid, an antihistamine and sulfoalkyl ether cyclodextrin derivatives to nasal and ophthalmic tissues.
  • CN 103784462 A discloses an ophthalmic preparation comprising bilastine and steroids as the active ingredients formulated in combination with auxiliary substances such as methylcellulose, cyclodextrin, sorbitol and alginic acid that enable such composition to be administered to the eye for the treatment of conjunctivitis.
  • auxiliary substances such as methylcellulose, cyclodextrin, sorbitol and alginic acid that enable such composition to be administered to the eye for the treatment of conjunctivitis.
  • beta-cyclodextrin as claimed.
  • WO 2007/117971 A2 relates to the treatment or prevention of ocular conditions with compositions of an H1 antagonist. This document refers to such topical preparation which has a longer duration of action and is advantageous because it may be instilled once daily. It fails to disclose bilastine.
  • US 2005/239745 A1 discloses topical ophthalmic formulations comprising ketotifen fumarate in combination with additional agents such as cyclodextrins, gelling agents (hyaluronic acid), tonicity agents (glycerin, sorbitol, mannitol) and polymers (cellulose and polyethylene glycol) that provide a comfortable preparation when instilled in the eye for treating ocular allergy.
  • additional agents such as cyclodextrins, gelling agents (hyaluronic acid), tonicity agents (glycerin, sorbitol, mannitol) and polymers (cellulose and polyethylene glycol) that provide a comfortable preparation when instilled in the eye for treating ocular allergy.
  • additional agents such as cyclodextrins, gelling agents (hyaluronic acid), tonicity agents (glycerin, sorbitol, mannitol) and polymers (cellulose and polyethylene glycol) that provide a comfortable preparation when instil
  • US 5 419 898 A relates to an anti-allergic composition for ophthalmic or nasal use comprising cetirizine and cyclodextrin compounds, which improve the stability of the drug.
  • Example 6 shows the results from a stability test of compositions comprising cyclodextrin. However, it fails to disclose bilastine.
  • the inventors of the present invention have surprisingly found that the ophthalmic formulations of the invention, which comprise bilastine result in the unexpected increase in the duration of the compound's ocular efficacy. These findings are particularly surprising when taking into account that such increase in efficacy is not observed in preclinical studies involving bilastine and the comparative antihistamine compounds olopatadine and azelastine.
  • the present invention thus provides for the first time a once-daily ophthalmic formulation comprising bilastine.
  • the invention provides an ophthalmic pharmaceutical composition comprising:
  • this invention refers to the aqueous ophthalmic pharmaceutical composition mentioned above for use in the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of H 1 histamine receptor, selected from an ocular allergic disorder or an allergic disease.
  • Another aspect of this invention refers to the aqueous ophthalmic pharmaceutical composition mentioned above and a further pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the inventors have surprisingly found that the combination of bilastine with at least a ⁇ -cyclodextrin and at least one pharmaceutically acceptable water-soluble gelling agent or an acceptable salt thereof, is optimal for ophthalmic applications, showing excellent prolonged action in the eye which allows the provision of a once-daily ophthalmic formulation comprising bilastine. Surprisingly, these results were not observable in preclinical trials, as shown in the Examples referring to preclinical and clinical studies.
  • the invention provides an ophthalmic pharmaceutical composition comprising:
  • the aqueous ophthalmic pharmaceutical composition of the invention comprises bilastine, of formula, or a pharmaceutically acceptable salt or solvate thereof.
  • This compound is the 2-[4-(2- ⁇ 4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl ⁇ ethyl)phenyl]-2-methylpropanoic acid, also known as bilastine.
  • the synthesis of bilastine has been described in documents EP 0818454 A1 , EP 0580541 A1 and EP 3040334 A1 .
  • Bilastine may be in the form of a salt or solvate, preferably pharmaceutically acceptable salts or solvates.
  • the invention also provides "salts" of the compounds described herein.
  • said salts can be acid addition salts, base addition salts or metal salts, and can be synthesized from the parent compounds containing a basic or acid moiety by means of conventional chemical processes known by the persons skilled in the art.
  • Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of the two.
  • Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred.
  • acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p- toluenesulfonate, camphorsulfonate, etc.
  • inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p- toluenesulfonate, camphorsulfonate,
  • base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • organic base salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • metal salts include, for example, sodium, potassium, calcium, magnesium, aluminium and lithium salts.
  • solvate according to this invention is to be understood as meaning any form of the active compound according to the invention which has another molecule (most likely a polar solvent) attached to it via non-covalent bonding.
  • examples of solvates include hydrates and alcoholates. Solvation methods are generally known in the state of the art.
  • the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon or a nitrogen by 15 N-enriched nitrogen are within the scope of this invention.
  • a concentration of at least 0.4% w/v means that there are more than 4 mg of bilastine completely dissolved, i.e, without any significant signs of precipitation, in just 1 mL of water. In the present invention, all the percentages are in w/v units unless otherwise stated.
  • bilastine is completely dissolved in the pharmaceutical composition of the invention at a concentration of at least 0.6% w/v, preferably at least 0.7% w/v. In another embodiment, bilastine is completely dissolved in the pharmaceutical composition of the invention at a concentration of at least 0.6% w/v but no more than 1.0% w/v.
  • the pharmaceutical composition comprises at least 0.4% w/v, at least 0.6% w/v, at least 0.7% w/v, at least 0.8% w/v, at least 0.9% w/v, or at least 0.6% but no more than 1.0% w/v of bilastine, wherein bilastine is completely dissolved.
  • the pharmaceutical composition comprises at least 0.4% w/v, at least 0.6% w/v, at least 0.7% w/v, at least 0.8% w/v, at least 0.9% w/v, or at least 0.6% but no more than 1.0% w/v of bilastine, wherein bilastine is completely dissolved.
  • bilastine is completely dissolved in the pharmaceutical composition of the invention at a concentration of at least 0.6% w/v but no more than 1.0% w/v.
  • a cyclodextrin is a cyclic structure composed of 5 or more ⁇ -D-glucopyranose units linked at the 1,4 positions, typically having 6 (a-cyclodextrin), 7 ( ⁇ -cyclodextrin), 8 (y-cyclodextrin) or 9 ( ⁇ -cyclodextrin) sugar units in one cyclodextrin molecule.
  • the MS value (average molar degree of substitution) is the average number of moles of substituent groups per glucopyranose mol.
  • the average number of substituents per ⁇ -cyclodextrin core can be calculated by multiplying the MS value by 7 (the ⁇ -cyclodextrin comprises 7 sugar units per cyclodextrin molecule).
  • An unambiguous notation for this value is the DS (degree of substitution).
  • cyclodextrin may refer to a cyclodextrin or a cyclodextrin derivative.
  • Cyclodextrins are commercially available or may be synthesized by methods well-known in the art. Examples of cyclodextrins include, but are not limited to, modified or unmodified ⁇ -, ⁇ -, ⁇ - and ⁇ -cyclodextrins.
  • the cyclodextrins of the present invention are ⁇ -cyclodextrins.
  • Derivatives of cyclodextrins and particularly of the ⁇ -cyclodextrins of the invention include those wherein some or all of the OH groups are converted to OR groups.
  • Said derivatives include those with C 1-6 alkyl groups such as e.g. methylated, ethylated, propylated and butylated cyclodextrins, wherein R is a methyl, ethyl, propyl or butyl group; those with hydroxyalkyl substituted groups such as e.g.
  • hydroxypropyl cyclodextrins or hydroxyethyl cyclodextrins wherein R is a -CH 2 CH(OH)CH 3 or a CH 2 CH 2 OH group; branched cyclodextrins such as maltose-bonded cyclodextrins; cationic cyclodextrins; quaternary ammonium; anionic cyclodextrins such as carboxymethyl cyclodextrins, cyclodextrin sulfates and cyclodextrin succinates; amphoteric cyclodextrins such as carboxymethyl/quaternary ammonium cyclodextrins.
  • hydroxyalkyl ether e.g. R is C 1-6 alkylenehydroxy
  • one or more sulfoalkyl ether e.g. R is C 2-6 alkyleneSO 3 -
  • carboxyalkyl e.g. R is C(O)C 1-6 alkyl
  • substituted phenoxy moieties tryptofan moieties; or mixtures thereof.
  • the total number of OR groups per cyclodextrin molecule is defined as the degree of substitution/modification.
  • the cyclodextrin of the ophthalmic pharmaceutical composition is a ⁇ -cyclodextrin.
  • the ⁇ -cyclodextrin is selected from the group consisting of C 1 -C 6 alkyl- ⁇ -cyclodextrin, C 1 -C 6 hydroxyalkyl ⁇ -cyclodextrin, C 1 -C 6 carboxyalkyl- ⁇ -cyclodextrin, carbonyl- ⁇ -cyclodextrin, C 2 -C 6 sulfoalkylether ⁇ -cyclodextrin and mixtures thereof.
  • the ⁇ -cyclodextrin is an C 1 -C 6 alkyl- ⁇ -cyclodextrin.
  • Preferred C 1 -C 6 alkyl- ⁇ -cyclodextrins include methyl- ⁇ -cyclodextrin; dimethyl- ⁇ -cyclodextrin; trimethyl- ⁇ -cyclodextrin; ethyl- ⁇ -cyclodextrin; diethyl- ⁇ -cyclodextrin; propyl- ⁇ -cyclodextrin; and butyl- ⁇ -cyclodextrin.
  • the ⁇ -cyclodextrin is selected from the group consisting of methyl- ⁇ -cyclodextrin or dimethyl- ⁇ -cyclodextrin.
  • C 1 -C 6 alkyl ⁇ -cyclodextrin derivatives preferably have a degree of substitution/modification of from about 1 to about 18, from about 3 to about 16, from about 4 to about 14, from about 4 to about 12.6, and more preferably from about 4 to 6.
  • the ⁇ -cyclodextrin is not an alkenyl- ⁇ -cyclodextrin, particularly the ⁇ -cyclodextrin is not hydroxybutenyl- ⁇ -cyclodextrin.
  • the cyclodextrin is a C 1 -C 6 hydroxyalkyl- ⁇ -cyclodextrin.
  • Preferred C 1 -C 6 hydroxyalkyl- ⁇ -cyclodextrins include hydroxyethyl- ⁇ -cyclodextrin; hydroxypropyl- ⁇ -cyclodextrin (which is equivalent to 2-hydroxypropyl- ⁇ -cyclodextrin) and 2-hydroxybutyl- ⁇ -cyclodextrin.
  • the cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin (HPBCD or HP- ⁇ -CD).
  • C 1 -C 6 hydroxyalkyl cyclodextrin derivatives and particularly the hydroxypropyl- ⁇ -cyclodextrin, preferably have a degree of substitution/modification of from about 1 to about 14, more preferably from about 4 to about 8.
  • the cyclodextrin is a C 1 -C 6 carboxyalkyl- ⁇ -cyclodextrin.
  • Preferred C 1 -C 6 carboxyalkyl- ⁇ -cyclodextrins for use herein include carboxymethyl- ⁇ -cyclodextrin and (2-carboxyethyl)- ⁇ -cyclodextrin.
  • the cyclodextrin is a C 2 -C 6 sulfoalkylether ⁇ -cydodextrin.
  • a preferred C 2 -C 6 sulfoalkylether- ⁇ -cyclodextrin for use herein is sulfobutylether- ⁇ -cyclodextrin.
  • C 2 -C 6 sulfoalkylether- ⁇ -cyclodextrin derivatives preferably have a degree of substitution/modification from about 1 to about 14, preferably from about 1 to about 7.
  • the cyclodextrin is a ⁇ -cyclodextrin selected from the group consisting of C 1 -C 6 alkyl- ⁇ -cyclodextrin, C 1 -C 6 hydroxyalkyl ⁇ -cyclodextrin, C 1 -C 6 carboxyalkyl- ⁇ -cyclodextrin, C 2 -C 6 sulfoalkylether ⁇ -cyclodextrin and mixtures thereof.
  • the cyclodextrin is a ⁇ -cyclodextrin selected from the group consisting of C 1 -C 6 hydroxyalkyl ⁇ -cyclodextrin, C 1 -C 6 carboxyalkyl- ⁇ -cyclodextrin, C 2 -C 6 sulfoalkylether ⁇ -cyclodextrin and mixtures thereof.
  • the cyclodextrin is a ⁇ -cyclodextrin selected from the group consisting of C 1 -C 6 hydroxyalkyl- ⁇ -cyclodextrins, C 2 -C 6 sulfoalkylether ⁇ -cyclodextrins and mixtures thereof.
  • the cyclodextrin is a pharmaceutically acceptable cyclodextrin.
  • the cyclodextrin is present in the composition in an amount from about 0.1% to about 50% w/v.
  • w/v means weight/volume percentage concentration (g/100 mL), e.g. when the cyclodextrin is present in the composition in an amount from about 0.1% to about 50% means that is present in an amount from about 1 mg/mL to about 500 mg/mL. In the present invention, all the percentages are in w/v units unless otherwise stated.
  • the cyclodextrin is present in an amount from about 0.25% to about 30%, from about 0.5% to about 25%, from about 1% to about 20%, from about 2% to about 15%, or from about 3% to about 10% w/v.
  • the cyclodextrin of the pharmaceutical composition of the invention is in a concentration of at least 5% w/v but no more than 15% w/v, i.e. from about 50 to 150 mg/mL. More preferably, the cyclodextrin is present in an amount of at least 8% but no more than 10% w/v. In another preferred embodiment, the composition of the invention comprises 9 % w/v of cyclodextrin.
  • Water-soluble gelling agents refer to substances which can increase the viscosity of an aqueous solution such as the ophthalmic pharmaceutical composition of the invention, without substantially changing its other properties, but which form a gel, dissolving in the liquid phase as a colloid mixture that forms a weakly cohesive internal structure.
  • the at least one gelling agent is a pharmaceutically acceptable gelling agent for ophthalmic purposes.
  • the at least one pharmaceutically acceptable water-soluble gelling agent or an acceptable salt thereof is selected from hyaluronic acid, Gellan gum, and mixtures thereof.
  • the at least one pharmaceutically acceptable water-soluble gelling agent is hyaluronic acid or an acceptable salt thereof.
  • the gelling agent or an acceptable salt thereof is present in the aqueous composition of the invention in an amount from about 0.001% w/v to about 2% w/v, preferably from about 0.003% w/v to about 1% w/v.
  • the gelling agent is present in the aqueous composition of the invention in an amount of about 0.05%, about 0.1%, about 0.25 %, about 0.50%, about 0.75%, about 1%, about 1.5%, or about 2%. All the percentages are in w/v units unless otherwise stated.
  • the gelling agent is present in the aqueous composition of the invention in an amount of at least 0.05% w/v but no greater than 1% w/v, most preferably at 0.1 % w/v.
  • the ophthalmic pharmaceutical composition of the invention comprises:
  • the gelling agent is hyaluronic acid or a pharmaceutically acceptable salt thereof and has a molecular weight no greater than 600000 Da.
  • the molecular weight of the gelling agent can be measured according to known techniques in the art.
  • the average molecular weight of the hyaluronic acid or a pharmaceutically acceptable salt thereof may be determined using size exclusion chromatography coupled to multiangle laser light scattering (SEC-MALLS).
  • SEC-MALLS size exclusion chromatography coupled to multiangle laser light scattering
  • the average molecular weight of the hyaluronic acid or a pharmaceutically acceptable salt thereof may also be determined using the intrinsic viscosity and the Mark-Houwink relation.
  • the ophthalmic pharmaceutical composition of the invention further comprises at least one pharmaceutically acceptable water-soluble polymer as a viscosity agent, selected from the group consisting of an ether derivative of cellulose, polyethylene glycol, polyvinyl alcohol, and mixtures thereof.
  • Water-soluble polymers refer to hydrophilic polymers which are, at least partially, soluble in water.
  • the at least one water-soluble polymer is a pharmaceutically acceptable water-soluble polymer.
  • the at least one water-soluble-polymer is an ether derivative of cellulose, most preferably methylcellulose. In another embodiment the at least one water-soluble polymer is polyethylenglycol.
  • the water-soluble polymer is present in the aqueous composition of the invention in an amount from about 0.001% w/v to about 15% w/v, preferably from about 0.01% w/v to about 15% w/v. In particular embodiments the water-soluble polymer is present in the aqueous composition of the invention in an amount about 0.01%, about 0.05%, about 0.1%, about 0.25 %, about 0.50%, about 0.75%, about 1%, about 3%, about 5%, about 7%, about 10%, about 13% or about 15%. All the percentages are in w/v units unless otherwise stated.
  • the water-soluble polymer is an ether derivative of cellulose.
  • a cellulose ether derivative refers to cellulose wherein the hydroxyl groups of cellulose have been partially or fully substituted to provide cellulose ethers (-OR).
  • the ether derivative of cellulose is selected from the group consisting of alkyl celluloses, hydroxyalkyl celluloses, carboxyalkyl celluloses and mixtures thereof.
  • the ether derivative of cellulose is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, carboxyalkyl cellulose and mixtures thereof.
  • the cellulose ether derivative is alkyl cellulose.
  • Preferred alkyl celluloses for use herein include methylcellulose (MC), ethylcellulose, ethylmethyl cellulose and mixtures thereof.
  • the cellulose ether derivative is a hydroxyalkyl cellulose.
  • Preferred hydroxyalkyl celluloses for use herein include hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) and ethyl hydroxyethyl cellulose.
  • the cellulose ether derivative is a carboxyalkyl cellulose.
  • Preferred carboxyalkyl celluloses for use herein include carboxymethyl cellulose (CMC).
  • CMC and sodium carboxymethyl cellulose (CMCNa) are equivalents.
  • PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE).
  • PEG is a low-molecular-weight PEG, which means PEG having molecular-weight between 300-1000 g/mol.
  • the molecular weight of PEG is more preferably between 300 and 500 g/mol.
  • the molecular-weight is 400 g/mol, i.e., PEG400.
  • the composition has an osmolality comprised between about 200 mOsm/kg to about 640 mOsm/kg, preferably about 250 mOsm/kg to about 600 mOsm/kg. In a preferred embodiment, the osmolality is about 240 mOsm/kg to about 340 mOsm/kg.
  • the osmolality of the ophthalmic pharmaceutical solution of the invention may be measured using standard methods well-known in the art. Preferably but not limited, the osmolality of the ophthalmic pharmaceutical solution of the invention may be determined by the measurement of the freezing point depression of the solution with an osmometer.
  • the composition of the invention can further comprise osmolality agents or tonicity agents selected from glycerin, sorbitol, mannitol, erythriol, arabitol, xylitol, ribitol, galactitol, multitol, macrogol, lactitol, and mixtures thereof.
  • said osmolality agents or tonicity agents are in the aqueous composition of the invention in an amount of about 0.05%, about 0.1%, about 0.25 %, about 0.50%, about 0.75%, about 1%, about 1.5%, about 1.6%, about 2%, about 3%, about 5%, about 7%, about 10%, about 13% or about 15%.
  • said osmolality agents or tonicity agents are in the aqueous composition of the invention in an amount of less than 15%, 13%, 10%, 7%, 5%, 3% or 2%. All the percentages are in w/v units unless otherwise stated.
  • the osmolality agents or tonicity agents are in the aqueous composition of the invention in an amount of between 0.05% and 5% w/v.
  • the inventors have surprisingly found that the composition of the invention is stable and advantageously does not require the addition of preservative agents, such as benzalkonium chloride, imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol and sorbic acid, which are known to cause dry eye and eye irritation.
  • preservative agents such as benzalkonium chloride, imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol and sorbic acid, which are known to cause dry eye and eye irritation.
  • the ophthalmic pharmaceutical composition of the invention is devoid of preservatives.
  • the composition of the invention comprises glycerin.
  • Glycerin is synonym to glycerol or glycerine.
  • the glycerin is in the aqueous composition of the invention in an amount between 0.05% and 5% w/v, more preferably between 0.05% and 3% w/v.
  • the glycerin is present as a tonicity agent at a concentration not greater than 2.5%.
  • the composition of the invention comprises glycerin in an amount of about 1.6%, preferably of 1.61%. All the percentages are in w/v units unless otherwise stated.
  • the aqueous pharmaceutical composition of the invention has been preferably developed for ophthalmic uses and/or administration, i.e. the aqueous ophthalmic pharmaceutical composition is adapted to these purposes.
  • the physiological pH of the eye, particularly the human eye, is known to be between about 6.5-8.0.
  • the pharmaceutical composition has a pH value comprised between 4 and 9, both lower and upper limits included.
  • the pH of the aqueous ophthalmic pharmaceutical composition of the present invention is 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3 or 9.4.
  • pH value of 4 may also identified as corresponding to a pH range of from 3.6 to 4.4.
  • a pH value of 9 may also be identified as corresponding to a pH range of from 8.6 to 9.4.
  • the pH value of the pharmaceutical composition is 4.0, 5.5, 7.4, 8.0 or 9.0.
  • a pH-adjusting agent selected from the group consisting of hydrochloric acid, boric acid, acetic acid, sodium hydroxide, potassium hydroxide, or a combination thereof.
  • a buffering agent selected from the group consisting of acetate buffer, a citrate buffer, a phosphate buffer, a borate buffer, or a combination thereof.
  • composition has a pH in a range that maintains chemical, physical, and/or physiological stability of bilastine and is well-tolerated by the eye.
  • Bilastine has been found to be an antagonist of histamine H 1 receptor and would thus be useful in the treatment and/or prevention of diseases known to be susceptible to amelioration by antagonism of histamine H 1 receptor.
  • an aspect of the invention refers to an aqueous ophthalmic pharmaceutical composition as defined above for use in the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of H 1 histamine receptor, selected from an ocular allergic disorder or an allergic disease..
  • the invention is directed to an aqueous ophthalmic pharmaceutical composition as defined above for use in the treatment and/or prevention of an ocular allergic disorder or allergic disease.
  • an allergic disease or disorder selected from rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, ocular irritation, itchiness, redness, tearing, chemosis, keratitis sicca, keratoconjunctivitis sicca or dysfunctional tear syndrome.
  • the dry-eye syndrome includes keratitis sicca, keratoconjunctivitis sicca or dysfunctional tear syndrome.
  • the invention is directed to an aqueous ophthalmic pharmaceutical composition as defined above for use in the treatment and/or prevention of allergic conjunctivitis.
  • the invention is directed to an aqueous ophthalmic pharmaceutical composition as defined above for use in the treatment and/or prevention of dry eye syndrome.
  • the invention is directed to an aqueous ophthalmic pharmaceutical composition as defined above for use in the simultaneous treatment and/or prevention of allergic conjunctivitis and dry eye syndrome.
  • treatment means administration of a compound or formulation according to the invention to ameliorate or eliminate the disease or one or more symptoms associated with said disease.
  • Treatment also encompasses ameliorating or eliminating the physiological sequelae of the disease.
  • prevention means administration of a compound or formulation according to the invention to reduce the risk of acquiring or developing the disease or one or more symptoms associated with said disease.
  • aqueous ophthalmic pharmaceutical composition refers to a liquid pharmaceutical composition comprising water suitable for ocular use.
  • bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration of at least 0.4% w/v. In another embodiment, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration of at least 0.6% w/v, preferably at least 0.7%. In another embodiment, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration comprised between 0.6 to 1.0 w/v %, preferably at a concentration comprised between 0.6 to 0.9 w/v %, more preferably at a concentration comprised between 0.6 to 0.8%.
  • bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration of 0.6 % w/v.
  • w/v % means weight/volume percentage concentration (g/100 mL), e.g. when bilastine is present in the composition in an amount from about 0.6% to about 1.0% means that is present in an amount from about 6 mg/mL to about 10 mg/mL. In the present invention, all the percentages are in w/v units unless otherwise stated.
  • the amount of bilastine in the pharmaceutical composition of the invention is preferably above 4500 ⁇ g/mL, preferably above 6000 ⁇ g/mL, preferably above 6500 ⁇ g/mL, preferably above 7000 ⁇ g/mL, preferably above 7500 ⁇ g/mL, preferably above 8000 ⁇ g/mL, preferably above 8500 ⁇ g/mL, preferably above 9000 ⁇ g/mL, and more preferably above 9500 ⁇ g/mL.
  • the amount of bilastine in the pharmaceutical composition of the invention is lower than 10500 ⁇ g/mL
  • the aqueous ophthalmic pharmaceutical composition comprises bilastine, a ⁇ -cyclodextrin and hyaluronic acid or an acceptable salt thereof, wherein the bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition.
  • the aqueous ophthalmic pharmaceutical composition comprises bilastine, hydroxypropyl- ⁇ -cyclodextrin and hyaluronic acid or an acceptable salt thereof, wherein the bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition.
  • therapeutically effective amount means that amount of a medicament which when administered supplies an amount of one or more pharmaceutically active agents contained therein to provide a therapeutic benefit in the treatment or management of a disease or disease state.
  • the pharmaceutical composition of the invention comprises a therapeutically effective amount of bilastine.
  • aqueous ophthalmic pharmaceutical composition of the invention may comprise further pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient refers to a vehicle, diluent, or adjuvant that is administered with the active ingredient.
  • Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similar. Water or saline aqueous solutions and aqueous dextrose and glycerin solutions, particularly for injectable solutions, are preferably used as vehicles. Suitable pharmaceutical vehicles are described in " Remington's Pharmaceutical Sciences” by E.W. Martin, 21st Edition, 2005 .
  • excipients and auxiliary substances necessary to manufacture the desired pharmaceutical form of administration of the pharmaceutical composition of the invention will depend, among other factors, on the elected administration pharmaceutical form.
  • Said pharmaceutical forms of administration of the pharmaceutical composition will be manufactured according to conventional methods known by the skilled person in the art.
  • a review of different active ingredient administration methods, excipients to be used and processes for producing them can be found in " Tratado de Farmacia Galénica", C. Faul ⁇ i Trillo, Luzán 5, S.A. de Ediations, 1993 .
  • pharmaceutically acceptable refers to compositions and molecular entities that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavourable reaction as gastric disorders, dizziness and suchlike, when administered to a human or animal.
  • pharmaceutically acceptable means it is approved by a regulatory agency of a state or federal government or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • Formulations disclosed herein also optionally further comprise one or more ophthalmic excipients.
  • Ophthalmic excipients include, by way of non-limiting examples, at least one agent selected from a mucoadhesive, a preservative, a pH-adjusting agent, a tonicity-adjusting agent, a buffering agent, an antioxidant, a chelating agent, an antimicrobial preservative, a chemical preservative, a viscosity agent or a combination thereof.
  • the ophthalmic composition further comprises a water-soluble polymer, as defined above.
  • composition of the invention does not comprise a corticosteroid.
  • the ophthalmic pharmaceutical composition comprises:
  • the ophthalmic pharmaceutical composition comprises:
  • the ophthalmic pharmaceutical composition comprises:
  • Table 1 below provides a listing of exemplary ingredients suitable for an exemplary preferred formulation of the ophthalmic composition of the present invention and a desired weight/volume percentage for those ingredients. It shall be understood that the following Table 1 is exemplary and that certain ingredients may be added or removed from the Table and concentrations of certain ingredients may be changed while the formulation can remain within the scope of the present invention, unless otherwise specifically stated. Table 1. Exemplary preferred formulation of the ophthalmic composition of the present invention and a desired weight/volume percentage for those ingredients.
  • compositions include any liquid composition for topical administration to the eye.
  • Liquid forms are solutions, suspensions or emulsions.
  • suitable preparations for topical administration to the eye include ophthalmic drops (i.e. eye drops or artificial tears), ophthalmic emulsions, and ophthalmic ointments.
  • ophthalmic drops i.e. eye drops or artificial tears
  • ophthalmic emulsions i.e. eye drops or artificial tears
  • ophthalmic ointments i.e. ophthalmic emulsions
  • ophthalmic ointments examples include ophthalmic preparations as ophthalmic drops.
  • Ophthalmic preparations may include a suitable antimicrobial agent.
  • the ophthalmic preparations do not include a preservative.
  • the ophthalmic preparations do not include a preservative selected from benzalkonium chloride, imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol and sorbic acid.
  • a preservative selected from benzalkonium chloride, imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol and sorbic acid.
  • the present invention provides an ophthalmic pharmaceutical composition as defined above.
  • said ophthalmic pharmaceutical composition is a once-daily pharmaceutical composition.
  • bilastine supplied by Sai Life Sciences, Batch 5000011325
  • methylcellulose 1500 MC1500
  • Adarma methylcellulose 1500
  • Gellan gum GG
  • sodium hyaluronate Caref
  • glycerin Merck-Millipore.
  • the water used in the following examples was purified water obtained using an Elix® water purification system from Merck-Millipore.
  • Example 1 Stability of over 6.5 mg/mL bilastine at 25°C, in the presence of 9% of different ⁇ -cyclodextrins in aqueous solutions at different pH values.
  • This example shows the stability of bilastine solutions at a concentration of over 6.5 mg/mL (0.65 % w/v) in the presence of 9.0% w/v of the five cyclodextrins ⁇ -CD, HP- ⁇ -CD, CM- ⁇ -CD, DM- ⁇ -CD and SBE- ⁇ -CD in aqueous solutions at different pH values.
  • Each pH value was obtained by adjustment starting from a basic solution as follows.
  • Each Eppendorf was introduced into an incubator (VWR® Incubating Mini Shaker) under constant stirring (100 rpm) and it was incubated at 30 °C for 1 hour. Then, 1.5 mL samples of each Eppendorf were centrifuged for 0.5 hours at 12,500 rpm (SIGMA 2-16P thermostated centrifuge) to eliminate solid particles of bilastine. Samples of the supernatant were appropriately diluted (1:100) to determine the concentration of bilastine. The concentration of bilastine was measured using a diode array spectrophotometer Hewlett Packard 8452A. Assays were performed in triplicate. Results are shown below. Table 2.
  • compositions of the invention were measured by positron emission tomography (PET) scans.
  • the compositions varied in their content of viscosity and tonicity agents: methylcellulose and glycerin; and gelling agent: sodium hyaluronate and/or Gellan gum.
  • the addition of the positron-emitting tracer 18 FDG allowed measuring the average retention time of each composition in the rat's ocular tissue.
  • Table 4 Ocular Average Retention Time (ART) of compositions of the invention comprising bilastine 0.4% w/v and HPB 9%.
  • Table 4 shows that the longest retention time, or ocular bioadhesion, is achieved when sodium hyaluronate (HA), Gellan gum (GG) or a mixture of AH and GG are used in combination with bilastine and HPB cyclodextrin both with and without methylcellulose (MC) and glycerin. Therefore, the results show that at least GG or HA are suitable for increasing the ocular retention time of the composition comprising bilastine and HPB and, optionally, MC and glycerin. The results are shown in Figure 3 .
  • HA sodium hyaluronate
  • GG Gellan gum
  • MC methylcellulose
  • Two aqueous ophthalmic formulations of bilastine were prepared at a bilastine concentration of 0.4% and 0.6% w/v. Both formulations also comprised HPB 90 mg/mL, methylcellulose 0.1 mg/mL, sodium hyaluronate 1 mg/mL and glycerin 16.1 mg/mL.
  • the ophthalmic formulations were applied by instillation in the right eye (25 ⁇ L), maintaining the animal immobilized for 2 to 3 minutes to ensure the permanence of the product in the conjunctival sac.
  • the left eye received the same volume of the correspondent vehicle or NaCl 0.9% in the case of marketed eye drops.
  • Each animal was its own positive control.
  • the result of adding the individual scores of each parameter in each eye was considered as the average of the global conjunctivitis degree.
  • Formulations that did not reach statistical significance or those reaching statistical significance but that did antagonize the histamine effect in a percentage ⁇ 30% were considered inactive.
  • the mean values of total score in the control eye (left) and in the antihistamine-treated eye (right) were calculated.
  • Azelastine 0.5 mg/ml (Afluon®) was active 9 h after application (38.4 % inhibition of histamine-induced effects), but not after 12 h (19.2% inhibition).
  • Olopatadine 1 mg/mL (Opatanol®) provided a much longer duration of activity, as its inhibitory activity was observed 24 hours after dosing (38.0% inhibition).
  • bilastine 4 mg/mL (0.4% w/v) described above was prepared and the duration of action was determined.
  • the activity obtained with this formulation against histamine-induced conjunctivitis in guinea pigs remains significant up to 9 hours after its application (36.4% inhibition, Figure 4 ).
  • bilastine 6 mg/mL (0.6% w/v) described above was also prepared and its activity compared with that of the bilastine 4 mg/mL.
  • the results obtained indicate a scarce improvement in terms of inhibition percentages with the highest bilastine concentration both after 9 hours (40.5 and 36.4% inhibition) and 12 h dosing (29.0 and 20.4% inhibition). No statistical differences were found at any time.
  • olopatadine 1 mg/mL showed a strong activity (75.9 and 63.9% of inhibition at 9 and 12 hours after dosing respectively). It was concluded that the increase in the concentration of bilastine did not entail a notable improvement in terms of effectiveness and duration of the effect.
  • aqueous ophthalmic formulations of bilastine were prepared at a bilastine concentration of 0.2% w/v, 0.4% and 0.6% w/v.
  • the vehicle formulation did not comprise any bilastine.
  • the excipients were as indicated above in Table 1, i.e., also comprised HPB 90 mg/mL, methylcellulose 0.1 mg/mL, sodium hyaluronate 1 mg/mL and glycerin 16.1 mg/mL.
  • the CAC® is a standardized model for studying investigational therapies for ocular allergy.
  • the CAC® induces the signs and symptoms of ocular allergy (e.g. ocular redness, swelling tearing, and ocular itching) in a controlled manner by direct administration of allergen to the conjunctiva.
  • One dose (one drop in each eye) of the assigned test article was administered 15 minutes, 8, or 16 hours prior to a CAC® test and allergic conjunctivitis sign and symptom assessments.
  • the study consisted of eight office visits over a period of approximately six to ten weeks. Efficacy was assessed using the CAC® model performed by ORA, Inc., Andover, Massachusetts, United States, 01810.
  • the CAC® model includes a screening, treatment and follow-up period.
  • the treatment period began at Visit 4a after subjects were randomized. At this visit, subjects received an in-office dose of the treatment they were randomized to receive. Approximately 16 hours post-instillation of study medication, subjects underwent CAC® at Visit 4b. At Visit 5a, subjects received an in-office dose of the same study medication. Approximately 8 hours post-instillation of study medication, subjects underwent CAC® at Visit 5b. Subjects received a final dose of study medication at Visit 6 approximately 15 minutes prior to CAC®.
  • each patient is dosed with drug or vehicle and exposed to allergen at specific challenge times.
  • the challenge times for the study were 15 minutes, 8 hours and 16 hours after dosing. Thereafter, itching was determined at determination times of 3, 5 and 7 minutes after challenge times at Visits 4b (16 hours post instillation of study medication), 5b (8 hours post instillation of study medication), and 6 (15 minutes post instillation).
  • Patients were asked to rate their ocular itching on a scale of 0 to 4 (allowing half unit increments) to attain itching scores and in each score 0 was the least and 4 was greatest. Therefore, patients received three doses of drug or vehicle and each dose was followed by an allergen challenge and then ocular itching was evaluated by the subject as discussed.
  • Treatment success was defined as at least one concentration of bilastine ophthalmic solution showing clinical superiority over vehicle by at least 0.5 units for all 3 post-CAC® time points, and at least 1 unit for the majority of post-CAC® time points.
  • the results of those determinations at those time points are provided in Table 6 and that data is provided as a graph in Figures 5 and 6 .
  • Table 6 Mean ocular itching score treatment differences calculated as Active-Vehicle using least square means (LSMeans).
  • Visit Visit 4b (16-hour duration) Visit 5b (8-hour duration) Visit 6 (15-minute duration) Time Point (minutes) 3 5 7 3 5 7 3 5 7
  • bilastine at a concentration of 0.6% w/v was the only tested concentration that was clinically and statistically efficacious when given 16 hours prior to CAC® (Visits 4b) for the treatment of ocular itching. This data is particularly surprising since, prior to this CAC® study, there was no indication that a formulation of bilastine at a concentration of 0.6% w/v would be highly effective reducing ocular itching at 16 hours post instillation.
  • olopatadine 1 mg/mL (Opatanol®) provided a much longer duration of activity, as its inhibitory activity was observed 24 hours after dosing.
  • the state of the art confirms in a human clinical trial the extended duration of action of an olopatadine 0.2% solution in this histamine-induced vascular leakage animal model ( Vogelson CT, Abelson MB, Pasquine T, Stephens DM, Gamache DA, Gross RD, Robertson SM, Yanni JM. Preclinical and clinical antiallergic effect of olopatadine 0.2% solution 24 hours after topical ocular administration. Allergy Asthma Proc. 2004, 25: 69-75 ).
  • bilastine and olopatadine anti-histaminic effects were compared in a guinea pig model of histamine-induced conjunctival vascular permeability.
  • guinea pigs were given a subconjunctival histamine challenge after pre-treatment with topical drug or vehicle and i.v. loading with Evans blue dye.
  • patients with difficulty managing their allergic conjunctivitis symptoms with one dose of their antiallergic ocular drops and consequently having to use a second dose may benefit from the increased convenience of a once-daily dosing regimen of a formulation with a content of bilastine of at least 0.4% w/v.
  • Example 5 Ocular in vivo biodistribution of ophthalmic formulations
  • Example 4 confirms the results of example 4 by showing that the bilastine in the ophthalmic formulations of the invention, upon administration to rabbit eyes, is mainly found in the conjunctiva, when compared to the cornea, iris, retina and crystalline lens tissues.
  • aqueous ophthalmic formulations of bilastine were prepared at a bilastine concentration of 0.6% w/v.
  • the excipients were as indicated above in Table 1, i.e., also comprised HPB 90 mg/mL, methylcellulose 0.1 mg/mL, sodium hyaluronate 1 mg/mL and glycerin 16.1 mg/mL.
  • the ophthalmic formulation was placed directly on both eyes of each animal by means of an automatic pipette. A new pipette tip was used for each eye.
  • the eyes of the test animals were not washed after instillation. Animals were weighed before administration and observed after administration to record any possible clinical sign.
  • Bilastine concentration was determined by LC-MS/MS.
  • the analytical methods involved protein precipitation for plasma and involved dilution for other matrices followed by LC-MS/MS analysis using F21201RR (Bilastine-d6) as internal standard.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (15)

  1. Composition pharmaceutique aqueuse à usage ophtalmique comprenant :
    a) au moins 0,4 % p/v mais pas plus de 1,0 % p/v de bilastine, ou d'un de ses sels ou solvates pharmaceutiquement acceptables, où la bilastine ou son sel ou solvate est complètement dissous dans la composition pharmaceutique aqueuse à usage ophtalmique ;
    b) au moins une β-cyclodextrine choisie dans le groupe constitué par la β-cyclodextrine non modifiée, une (alkyle en C1 à C6)-β-cyclodextrine, une (hydroxyalkyle en C1 à C6)-β-cyclodextrine, une carboxy(alkyle en C1 à C6)-β-cyclodextrine, la carbonyl-β-cyclodextrine, une (sulfoalkyléther en C2 à C6)-β-cyclodextrine, et leurs mélanges ; et
    c) au moins un agent gélifiant soluble dans l'eau pharmaceutiquement acceptable ou un de ses sels acceptables, choisi dans le groupe constitué par l'acide hyaluronique, la gomme gellane et leurs mélanges ;
    et dans laquelle la valeur de pH de la composition est comprise entre 4 et 9, bornes comprises.
  2. Composition pharmaceutique à usage ophtalmique selon la revendication 1, dans laquelle l'au moins une β-cyclodextrine est choisie dans le groupe constitué par la β-cyclodextrine non modifiée, une (alkyle en C1 à C6)-β-cyclodextrine, l'hydroxyéthyl-β-cyclodextrine, l'hydroxypropyl-β-cyclodextrine, la 2-hydroxybutyl-β-cyclodextrine, une carboxy(alkyle en C1 à C6)-β-cyclodextrine, la carbonyl-β-cyclodextrine, une (sulfoalkyléther en C2 à C6)-β-cyclodextrine, et leurs mélanges.
  3. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 ou 2, comprenant au moins 0,6 % p/v de bilastine ou d'un de ses sels ou solvates pharmaceutiquement acceptables, où la bilastine ou son sel ou solvate est complètement dissous dans la composition pharmaceutique aqueuse à usage ophtalmique.
  4. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 3, comprenant :
    a) au moins 0,6 % p/v mais pas plus de 1,0 % p/v de bilastine ou d'un de ses sels ou solvates pharmaceutiquement acceptables, où la bilastine ou son sel ou solvate est complètement dissous dans la composition pharmaceutique aqueuse à usage ophtalmique ;
    b) au moins une β-cyclodextrine choisie dans le groupe constitué par la β-cyclodextrine non modifiée, une (alkyle en C1 à C6)-β-cyclodextrine, l'hydroxyéthyl-β-cyclodextrine, l'hydroxypropyl-β-cyclodextrine, la 2-hydroxybutyl-β-cyclodextrine, une carboxy(alkyle en C1 à C6)-β-cyclodextrine, la carbonyl-β-cyclodextrine, une (sulfoalkyléther en C2 à C6)-β-cyclodextrine, et leurs mélanges, où la concentration de ladite β-cyclodextrine est d'au moins 5 % p/v mais non supérieure à 15 % p/v ; et
    c) de l'acide hyaluronique ou un de ses sels pharmaceutiquement acceptables, où la concentration dudit acide hyaluronique ou d'un de ses sels pharmaceutiquement acceptables est d'au moins 0,05 % p/v mais non supérieure à 1 % p/v.
  5. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 ou 3, dans laquelle la β-cyclodextrine est une (hydroxyalkyle en C1 à C6)-β-cyclodextrine choisie dans le groupe constitué par l'hydroxyéthyl-β-cyclodextrine, l'hydroxypropyl-β-cyclodextrine et la 2-hydroxybutyl-β-cyclodextrine.
  6. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 5, dans laquelle l'acide hyaluronique ou un de ses sels pharmaceutiquement acceptables a un poids moléculaire non supérieur à 600 000 Da.
  7. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 6, dans laquelle le pH est compris entre 5 et 8, bornes comprises.
  8. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 7, où la composition a une osmolalité comprise entre environ 250 mOsm/kg et environ 600 mOsm/kg.
  9. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 8, comprenant en outre un agent de tonicité choisi dans le groupe constitué par le glycérol, le sorbitol, le mannitol, l'érythritol, l'arabitol, le xylitol, le ribitol, le galactitol, le multitol, le macrogol, le lactitol, et leurs mélanges.
  10. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 9, comprenant :
    a) au moins 0,6 % p/v mais pas plus de 1,0 % p/v de bilastine ou d'un de ses sels ou solvates pharmaceutiquement acceptable, où la bilastine ou ledit sel ou solvate de celle-ci est complètement dissous dans la composition pharmaceutique aqueuse à usage ophtalmique ;
    b) au moins une (hydroxyalkyle en C1 à C6)-β-cyclodextrine, où la concentration de ladite β-cyclodextrine est d'au moins 5 % p/v mais non supérieure à 15 % p/v ;
    c) de l'acide hyaluronique ou un de ses sels pharmaceutiquement acceptables, où la concentration dudit acide hyaluronique ou d'un de ses sels pharmaceutiquement acceptables est d'au moins 0,05 % p/v mais non supérieure à 1 % p/v ;
    d) de 0,001 % p/v à 15 % p/v d'au moins un polymère soluble dans l'eau pharmaceutiquement acceptable, choisi dans le groupe constitué par un dérivé éther de cellulose, le polyéthylèneglycol, le poly(alcool vinylique), et leurs mélanges ; et
    e) de 0,05 % p/v à 5 % p/v d'au moins un agent de tonicité choisi dans le groupe constitué par le glycérol, le sorbitol, le mannitol, l'érythritol, l'arabitol, le xylitol, le ribitol, le galactitol, le multitol, le macrogol, le lactitol, et leurs mélanges.
  11. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 10, comprenant :
    a) au moins 0,6 % p/v mais pas plus de 1,0 % p/v de bilastine ou d'un de ses sels ou solvates pharmaceutiquement acceptables, où la bilastine ou ledit sel ou solvate de celle-ci est complètement dissous dans la composition pharmaceutique aqueuse à usage ophtalmique ;
    b) au moins une (hydroxyalkyle en C1 à C6)-β-cyclodextrine, où la concentration de ladite β-cyclodextrine est d'au moins 5 % p/v mais non supérieure à 15 % p/v ;
    c) de l'acide hyaluronique ou un de ses sels pharmaceutiquement acceptables, où la concentration dudit acide hyaluronique ou d'un de ses sels pharmaceutiquement acceptables est d'au moins 0,05 % p/v mais non supérieure à 1 % p/v ;
    d) de 0,001 % p/v à 15 % p/v d'un dérivé éther de cellulose ; et
    e) de 0,05 % p/v à 5 % p/v de glycérol.
  12. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 11, comprenant :
    a) au moins 0,6 % p/v mais pas plus de 1,0 % p/v de bilastine ou d'un de ses sels ou solvates pharmaceutiquement acceptables, où la bilastine ou ledit sel ou solvate de celle-ci est complètement dissous dans la composition pharmaceutique aqueuse à usage ophtalmique ;
    b) au moins une (hydroxyalkyle en C1 à C6) -β-cyclodextrine, où la concentration de ladite β-cyclodextrine est d'au moins 5 % p/v mais non supérieure à 15 % p/v ;
    c) de l'acide hyaluronique ou un de ses sels pharmaceutiquement acceptables, où la concentration dudit acide hyaluronique ou d'un de ses sels pharmaceutiquement acceptables est d'au moins 0,05 % p/v mais non supérieure à 1 % p/v ;
    d) de 0,005 % p/v à 0,1 % p/v de méthylcellullose ; et
    e) de 0,5 % p/v à 2 % p/v de glycérol.
  13. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 12, caractérisée en ce qu'il s'agit d'une composition pharmaceutique à usage ophtalmique devant être administrée une fois par jour.
  14. Composition pharmaceutique à usage ophtalmique selon l'une quelconque des revendications 1 à 13, pour une utilisation dans le traitement et/ou la prévention d'un trouble ou d'une maladie susceptible d'être amélioré par un antagonisme du récepteur d'histamine H1, choisi parmi un trouble allergique oculaire et une maladie allergique.
  15. Composition pharmaceutique à usage ophtalmique pour une utilisation selon la revendication 14, dans laquelle le trouble ou la maladie susceptible d'être amélioré par un antagonisme du récepteur d'histamine H1 est une rhinite, une rhinoconjonctivite, une conjonctivite allergique, une kératoconjonctivite printanière, une kératoconjonctivite atopique, une conjonctivite à papilles géantes, une irritation oculaire, une démangeaison, une rougeur, un larmoiement, un chémosis, une kératite sèche, une kératoconjonctivite sèche ou un syndrome du larmoiement dysfonctionnel.
EP19701154.7A 2018-01-18 2019-01-09 Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant Active EP3740191B1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
SI201930076T SI3740191T1 (sl) 2018-01-18 2019-01-09 Očesna sestava, obsegajoča bilastin, beta ciklodekstrin in vsaj eno želirno sredstvo
EP21169956.6A EP3915539A1 (fr) 2018-01-18 2019-01-09 Compositions ophtalmiques de composés de benzimidazole à dose quotidienne unique
PL19701154T PL3740191T3 (pl) 2018-01-18 2019-01-09 Kompozycje oftalmiczne zawierające bilastynę, beta-cyklodektrynę i co najmniej jeden środek żelatujący
HRP20211037TT HRP20211037T1 (hr) 2018-01-18 2021-06-30 Oftalmološki sastavi koji sadrže bilastin, beta-ciklodekstrin i bar jedno sredstvo za geliranje

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18382021 2018-01-18
PCT/EP2019/050433 WO2019141563A1 (fr) 2018-01-18 2019-01-09 Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP21169956.6A Division EP3915539A1 (fr) 2018-01-18 2019-01-09 Compositions ophtalmiques de composés de benzimidazole à dose quotidienne unique

Publications (2)

Publication Number Publication Date
EP3740191A1 EP3740191A1 (fr) 2020-11-25
EP3740191B1 true EP3740191B1 (fr) 2021-04-28

Family

ID=61017875

Family Applications (2)

Application Number Title Priority Date Filing Date
EP19701154.7A Active EP3740191B1 (fr) 2018-01-18 2019-01-09 Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant
EP21169956.6A Withdrawn EP3915539A1 (fr) 2018-01-18 2019-01-09 Compositions ophtalmiques de composés de benzimidazole à dose quotidienne unique

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP21169956.6A Withdrawn EP3915539A1 (fr) 2018-01-18 2019-01-09 Compositions ophtalmiques de composés de benzimidazole à dose quotidienne unique

Country Status (27)

Country Link
US (1) US20210128544A1 (fr)
EP (2) EP3740191B1 (fr)
JP (1) JP7309729B2 (fr)
KR (1) KR102695627B1 (fr)
CN (1) CN111727035B (fr)
AR (1) AR114216A1 (fr)
AU (1) AU2019209214B2 (fr)
BR (1) BR112020014265A2 (fr)
CA (1) CA3088740A1 (fr)
CL (1) CL2020001895A1 (fr)
CO (1) CO2020009992A2 (fr)
CY (1) CY1124270T1 (fr)
DK (1) DK3740191T3 (fr)
EA (1) EA202091725A1 (fr)
ES (1) ES2878107T3 (fr)
HR (1) HRP20211037T1 (fr)
HU (1) HUE054594T2 (fr)
LT (1) LT3740191T (fr)
MA (1) MA51612B1 (fr)
MX (1) MX2020007692A (fr)
PL (1) PL3740191T3 (fr)
PT (1) PT3740191T (fr)
SA (1) SA520412443B1 (fr)
SI (1) SI3740191T1 (fr)
TW (1) TWI833727B (fr)
UY (1) UY38055A (fr)
WO (1) WO2019141563A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2023221541A1 (en) 2022-02-17 2024-08-08 Faes Farma, S.A. Bilastine composition for once-daily parenteral administration
CN115970066B (zh) * 2022-12-29 2024-09-27 成都爱睿康乐医疗器械有限公司 基于主客体相互作用的载药纳米凝胶生物润滑剂及其制备方法和应用

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1229075B (it) * 1985-04-05 1991-07-17 Fidia Farmaceutici Medicamenti per uso topico, ottenuti tramite l'impiego dell'acido ialuronico
ES2048109B1 (es) 1992-07-20 1994-12-16 Espanola Prod Quimicos Procedimiento de preparacion de nuevos derivados piperidicos del bencimidazol.
JP3527256B2 (ja) 1992-12-09 2004-05-17 ロート製薬株式会社 抗アレルギー点眼剤
TW401300B (en) * 1992-12-25 2000-08-11 Senju Pharma Co Antiallergic composition for ophthalmic or nasal use
ES2124167B1 (es) 1996-06-04 1999-09-16 Espanola Prod Quimicos Nuevos derivados del bencimidazol con actividad antihistaminica.
DE10161149B4 (de) 2001-12-12 2007-03-08 Ursapharm Arzneimittel Gmbh & Co. Kg Verwendung von Heparin-haltigem Ophthalmikum
DE60216641T2 (de) 2002-04-19 2007-09-27 Faes Farma S.A. Polymorph von 4-ä2-ä4-ä1-(2-ethoxyethyl)-1h-benzimidazol-2-ylü-1-piperidinylüethylü-alpha, alpha-dimethylbenzolessigsäure
US20050239745A1 (en) * 2004-03-03 2005-10-27 Ophthalmic Research Associates, Inc. Novel topical ophthalmic formulations
US7247623B2 (en) * 2005-08-19 2007-07-24 Inspire Pharmaceuticals, Inc. Method of treating dry eye disease with non-drying antihistamines
WO2007047253A2 (fr) 2005-10-11 2007-04-26 Eastman Chemical Company Formulations pharmaceutiques de cyclodextrines et composes antifongiques de type azole
ES2594655T3 (es) 2006-03-31 2016-12-21 Vistakon Pharmaceuticals, Llc Tratamiento de alergias oculares
UA94938C2 (ru) * 2006-03-31 2011-06-25 ВИСТЕКОН ФАРМАСЬЮТИКАЛС, ЭлЭлСи Офтальмическая композиция для лечения клинических симптомов глазной аллергии, которая содержит алкафтадин или его производное (варианты)
CN101795565A (zh) 2007-06-28 2010-08-04 锡德克斯药物公司 皮质类固醇水溶液的鼻部和眼部给药
CA2754996A1 (fr) 2009-03-17 2010-09-23 Aciex Therapeutics, Inc. Formulations ophtalmiques de ketotifene et procedes d'utilisation
TWI544922B (zh) 2011-05-19 2016-08-11 愛爾康研究有限公司 高濃度歐羅派特錠（ｏｌｏｐａｔａｄｉｎｅ）眼用組成物
CN103110575B (zh) * 2013-03-07 2014-11-05 宁夏康亚药业有限公司 一种美洛昔康滴眼液及其制备方法和应用
WO2014150899A1 (fr) 2013-03-15 2014-09-25 Chapin Matthew J Formulations ophtalmiques topiques pour traiter la migraine
CN103784462A (zh) * 2014-02-25 2014-05-14 宋俊智 包含比拉斯汀及甾族化合物的药物制剂
EP3040334A1 (fr) 2014-12-29 2016-07-06 Faes Farma, S.A. Nouveaux dérivés de benzimidazole en tant qu'agents antihistaminiques

Also Published As

Publication number Publication date
KR20200111727A (ko) 2020-09-29
CN111727035A (zh) 2020-09-29
WO2019141563A1 (fr) 2019-07-25
SI3740191T1 (sl) 2021-09-30
EP3915539A1 (fr) 2021-12-01
EA202091725A1 (ru) 2020-10-12
LT3740191T (lt) 2021-08-10
PL3740191T3 (pl) 2021-11-29
US20210128544A1 (en) 2021-05-06
AU2019209214A1 (en) 2020-08-13
CY1124270T1 (el) 2022-07-22
CO2020009992A2 (es) 2021-01-18
MX2020007692A (es) 2020-09-14
TW201932110A (zh) 2019-08-16
AU2019209214B2 (en) 2023-11-23
MA51612A (fr) 2020-11-25
JP2021511317A (ja) 2021-05-06
JP7309729B2 (ja) 2023-07-18
UY38055A (es) 2019-08-30
ES2878107T3 (es) 2021-11-18
PT3740191T (pt) 2021-07-09
HRP20211037T1 (hr) 2021-10-01
TWI833727B (zh) 2024-03-01
KR102695627B1 (ko) 2024-08-16
CN111727035B (zh) 2024-05-28
EP3740191A1 (fr) 2020-11-25
AR114216A1 (es) 2020-08-05
DK3740191T3 (da) 2021-06-07
CL2020001895A1 (es) 2020-12-04
BR112020014265A2 (pt) 2020-12-08
MA51612B1 (fr) 2021-06-30
SA520412443B1 (ar) 2022-09-01
HUE054594T2 (hu) 2021-09-28
CA3088740A1 (fr) 2019-07-25

Similar Documents

Publication Publication Date Title
US10987352B2 (en) Ophthalmic formulations of cetirizine and methods of use
US20110105450A1 (en) Ophthalmic formulations of fluticasone and methods of use
US8569273B2 (en) Ophthalmic formulations of cetirizine and methods of use
EP3740191B1 (fr) Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant
EA043904B1 (ru) Офтальмологическая композиция, содержащая биластин, бета-циклодекстрин и по крайней мере одно желатинирующее вещество
AU2023221541A2 (en) Bilastine composition for once-daily parenteral administration

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200708

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20210127

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40034170

Country of ref document: HK

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: TN

Ref legal event code: VAGR

Ref document number: TN/P/2021/000100

Country of ref document: TN

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1386308

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210515

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602019004293

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20210602

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20211037T

Country of ref document: HR

Ref country code: MA

Ref legal event code: VAGR

Ref document number: 51612

Country of ref document: MA

Kind code of ref document: B1

REG Reference to a national code

Ref country code: FI

Ref legal event code: FGE

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Ref document number: 3740191

Country of ref document: PT

Date of ref document: 20210709

Kind code of ref document: T

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20210702

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E020935

Country of ref document: EE

Effective date: 20210610

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 37525

Country of ref document: SK

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20210401693

Country of ref document: GR

Effective date: 20210813

REG Reference to a national code

Ref country code: NO

Ref legal event code: T2

Effective date: 20210428

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E054594

Country of ref document: HU

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20211037

Country of ref document: HR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2878107

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20211118

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210828

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210428

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20211037

Country of ref document: HR

Payment date: 20211220

Year of fee payment: 4

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210428

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602019004293

Country of ref document: DE

VS25 Lapsed in a validation state [announced via postgrant information from nat. office to epo]

Ref country code: MD

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210428

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20220131

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210828

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210428

VSFP Annual fee paid to validation state [announced via postgrant information from national office to epo]

Ref country code: TN

Payment date: 20220131

Year of fee payment: 4

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20211037

Country of ref document: HR

Payment date: 20221221

Year of fee payment: 5

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230420

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 1386308

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210428

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SK

Payment date: 20231219

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MC

Payment date: 20231221

Year of fee payment: 6

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20211037

Country of ref document: HR

Payment date: 20231219

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: RO

Payment date: 20231221

Year of fee payment: 6

Ref country code: PT

Payment date: 20231219

Year of fee payment: 6

Ref country code: MT

Payment date: 20231221

Year of fee payment: 6

Ref country code: LV

Payment date: 20231219

Year of fee payment: 6

Ref country code: LT

Payment date: 20231219

Year of fee payment: 6

Ref country code: HR

Payment date: 20231219

Year of fee payment: 6

Ref country code: EE

Payment date: 20231219

Year of fee payment: 6

Ref country code: CZ

Payment date: 20231220

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20231228

Year of fee payment: 6

Ref country code: NL

Payment date: 20240126

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20240129

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20240126

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240205

Year of fee payment: 6

Ref country code: IE

Payment date: 20240129

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20231220

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210428

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: HU

Payment date: 20231222

Year of fee payment: 6

Ref country code: FI

Payment date: 20240125

Year of fee payment: 6

Ref country code: DE

Payment date: 20240129

Year of fee payment: 6

Ref country code: CY

Payment date: 20231221

Year of fee payment: 6

Ref country code: BG

Payment date: 20240129

Year of fee payment: 6

Ref country code: GB

Payment date: 20240129

Year of fee payment: 6

Ref country code: CH

Payment date: 20240202

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SI

Payment date: 20231220

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20240109

Year of fee payment: 6

Ref country code: SE

Payment date: 20240127

Year of fee payment: 6

Ref country code: NO

Payment date: 20240129

Year of fee payment: 6

Ref country code: IT

Payment date: 20240122

Year of fee payment: 6

Ref country code: FR

Payment date: 20240125

Year of fee payment: 6

Ref country code: DK

Payment date: 20240125

Year of fee payment: 6

Ref country code: BE

Payment date: 20240129

Year of fee payment: 6